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PubMed2006

Modeling AAA+ ring complexes from monomeric structures.

AAA+ proteins form large, ring-shaped complexes, which act as energy-dependent unfoldases of macromolecules. Many crystal structures of proteins in this superfamily have been determined, but mostly in monomeric or non-physiological oligomeric forms. The assembly of ring-shaped complexes from monomer coordinates is, therefore, of considerable interest. We have extracted structural features of complex formation relating to the distance of monomers from the central axis, their relative orientation and the molecular contacts at their interfaces from experimentally determined oligomers and have implemented a semi-automated modeling procedure based on RosettaDock into the iMolTalk server (http://protevo.eb.tuebingen.mpg.de/iMolTalk). As examples of this procedure, we present here models of Apaf-1, MalT and ClpB. We show that the recent EM-based model of the apoptosome is not compatible with the conserved structural features of AAA+ complexes and that the D1 and D2 rings of ClpB are most likely offset by one subunit, in agreement with the structure proposed for ClpA.

Adenosine Triphosphatases↗

PubMed1999

Significantly lower entropy estimates for natural DNA sequences.

If DNA were a random string over its alphabet {A, C, G, T}, an optimal code would assign two bits to each nucleotide. DNA may be imagined to be a highly ordered, purposeful molecule, and one might therefore reasonably expect statistical models of its string representation to produce much lower entropy estimates. Surprisingly, this has not been the case for many natural DNA sequences, including portions of the human genome. We introduce a new statistical model (compression algorithm), the strongest reported to date, for naturally occurring DNA sequences. Conventional techniques code a nucleotide using only slightly fewer bits (1.90) than one obtains by relying only on the frequency statistics of individual nucleotides (1.95). Our method in some cases increases this gap by more than fivefold (1.66) and may lead to better performance in microbiological pattern recognition applications. One of our main contributions, and the principle source of these improvements, is the formal inclusion of inexact match information in the model. The existence of matches at various distances forms a panel of experts which are then combined into a single prediction. The structure of this combination is novel and its parameters are learned using Expectation Maximization (EM). Experiments are reported using a wide variety of DNA sequences and compared whenever possible with earlier work. Four reasonable notions for the string distance function used to identify near matches, are implemented and experimentally compared. We also report lower entropy estimates for coding regions extracted from a large collection of nonredundant human genes. The conventional estimate is 1.92 bits. Our model produces only slightly better results (1.91 bits) when considering nucleotides, but achieves 1.84-1.87 bits when the prediction problem is divided into two stages: (i) predict the next amino acid-based on inexact polypeptide matches, and (ii) predict the particular codon. Our results suggest that matches at the amino acid level play some role, but a small one, in determining the statistical structure of nonredundant coding sequences.

Algorithms↗

PubMed1993

PROGEN: an automated modelling algorithm for the generation of complete protein structures from the alpha-carbon atomic coordinates.

A modelling algorithm (PROGEN) for the generation of complete protein atomic coordinates from only the alpha-carbon coordinates is described. PROGEN utilizes an optimal geometry parameter (OGP) database for the positioning of atoms for each amino acid of the polypeptide model. The OGP database was established by examining the statistical correlations between 23 different intra-peptide and inter-peptide geometric parameters relative to the alpha-carbon distances for each amino acid in a library of 19 known proteins from the Brookhaven Protein Database (BPDB). The OGP files for specific amino acids and peptides were used to generate the atomic positions, with respect to alpha-carbons, for main-chain and side-chain atoms in the modelled structure. Refinement of the initial model was accomplished using energy minimization (EM) and molecular dynamics techniques. PROGEN was tested using 60 known proteins in the BPDB, representing a wide spectrum of primary and secondary structures. Comparison between PROGEN models and BPDB crystal reference structures gave r.m.s.d. values for peptide main-chain atoms between 0.29 and 0.76 A, with a grand average of 0.53 A for all 60 models. The r.m.s.d. for all non-hydrogen atoms ranged between 1.44 and 1.93 A for the 60 polypeptide models. PROGEN was also able to make the correct assignment of cis- or trans-proline configurations in the protein structures examined. PROGEN offers a fully automatic building and refinement procedure and requires no special or specific structural considerations for the protein to be modelled.

Algorithms↗

PubMedDate not supplied

Fast automatic particle picking from cryo-electron micrographs using a locally normalized cross-correlation function: a case study.

Recent progress in single-particle reconstruction methods and cryo-EM techniques has led to the determination of macromolecular structures with unprecedented resolution. The number of particles that goes into the reconstruction is a key determinant in achieving high resolution. Interactive manual picking of particles from an electron micrograph is a very time-consuming, tedious, and inefficient process. We have implemented a fast automatic particle picking procedure in the SPIDER environment. The procedure makes use of template matching schemes and employs a recently developed locally normalized correlation algorithm based on Fourier techniques. As a test, we have used this procedure to pick 70S Escherichia coli ribosomes from a cryo-electron micrograph. Different search strategies including use of a circular mask and asymmetric masks for different orientations of the particle have been explored, and their relative efficiencies are discussed. The results indicate that the procedure can be optimally used to pick ribosomes in a fully automatic way within the limit of selecting less than 10% false positives while missing about 15% of true positives.

Algorithms↗

PubMed2002

A latent autoregressive model for longitudinal binary data subject to informative missingness.

Longitudinal clinical trials often collect long sequences of binary data. Our application is a recent clinical trial in opiate addicts that examined the effect of a new treatment on repeated binary urine tests to assess opiate use over an extended follow-up. The dataset had two sources of missingness: dropout and intermittent missing observations. The primary endpoint of the study was comparing the marginal probability of a positive urine test over follow-up across treatment arms. We present a latent autoregressive model for longitudinal binary data subject to informative missingness. In this model, a Gaussian autoregressive process is shared between the binary response and missing-data processes, thereby inducing informative missingness. Our approach extends the work of others who have developed models that link the various processes through a shared random effect but do not allow for autocorrelation. We discuss parameter estimation using Monte Carlo EM and demonstrate through simulations that incorporating within-subject autocorrelation through a latent autoregressive process can be very important when longitudinal binary data is subject to informative missingness. We illustrate our new methodology using the opiate clinical trial data.

Algorithms↗

PubMed2005

Obligate heterodimerization of the archaeal Alba2 protein with Alba1 provides a mechanism for control of DNA packaging.

Organisms growing at elevated temperatures face a particular challenge to maintain the integrity of their genetic material. All thermophilic and hyperthermophilic archaea encode one or more copies of the Alba (Sac10b) gene. Alba is an abundant, dimeric, highly basic protein that binds cooperatively and at high density to DNA. Sulfolobus solfataricus encodes a second copy of the Alba gene, and the Alba2 protein is expressed at approximately 5% of the level of Alba1. We demonstrate by NMR, ITC, and crystallography that Alba2 exists exclusively as a heterodimer with Alba1 at physiological concentrations and that heterodimerization exerts a clear effect upon the DNA packaging, as observed by EM, potentially by changing the interface between adjacent Alba dimers in DNA complexes. A functional role for Alba2 in modulation of higher order chromatin structure and DNA condensation is suggested.

Algorithms↗

PubMed2005

Fast maximum-likelihood refinement of electron microscopy images.

MOTIVATION: Maximum-likelihood (ML) image refinement is a promising candidate to improve attainable resolution limits in 3D-EM. However, its large CPU requirements may prohibit application to 3D-structure optimization. RESULTS: We speeded up ML image refinement by reducing its search space over the alignment parameters. Application of this reduced-search approach to a cryo-EM dataset yielded practically identical results as the original approach, but in approximately one day instead of one week of CPU. AVAILABILITY: This work has been implemented in the public domain package Xmipp. Documentation and download instructions may be found at: http://www.cnb.uam.es/~bioinfo

Algorithms↗

PubMed1998

[Experienced anesthetists show better reaction to central gas supply dropout--an anesthesia simulator study].

The loss of pipeline pressure in a central gas supply system is a rare but potentially hazardous complication in anaesthesia and critical care. In an anaesthesia simulator study, reactions of 20 anaesthetists to this simulated critical incident were monitored and evaluated. A comparison between novice (n = 10) and experienced anaesthesia residents/consultants (n = 10) determined a significantly quicker and more on-target reaction by the experienced anaesthetists. Unlike older cycle system anaesthesia machines, update anaesthesia ventilators (CICERO EM, Dräger, Lübeck) do not permit manual ventilation of a patient in a "closed-system" once pipeline pressure drops to zero. In this highly hazardous event, the patient has to be ventilated by reservoir bag until a sufficient back-up system delivering high inspiratory oxygen concentrations can be installed, because he is otherwise prone to diffusion hypoxia. Installation of mandatory (anaesthesia-machine integrated) back-up systems for respirators without cycle systems would therefore increase patient safety. A general algorithm for loss of pipeline pressure can be described only after a back-up system has been installed.

Algorithms↗

PubMed2005

Modeling membrane proteins based on low-resolution electron microscopy maps: a template for the TM domains of the oxalate transporter OxlT.

The availability of both EM and high-resolution crystallographic data for several membrane proteins (MPs) permits a detailed evaluation of the ability of molecular modeling techniques to complement EM data in the development of models of MPs. A protocol for this purpose is presented, consisting of (1) identifying transmembrane (TM) domains from sequence; (2) assigning buried and lipid-exposed faces of the TM domains; and (3) assembling the TM domains into a bundle, based on geometric restraints obtained from the EM data. The protocol is validated by predicting the structures of several 7- and 12-TM MPs to within 3-5 A r.m.s.d. from their crystal structures. The protocol is applied to generate a model of the oxalate transporter OxlT, for which a high-resolution structure is not yet available.

Algorithms↗

PubMed2006

Inference for the dependent competing risks model with masked causes of failure.

The competing risks model is useful in settings in which individuals/units may die/fail for different reasons. The cause specific hazard rates are taken to be piecewise constant functions. A complication arises when some of the failures are masked within a group of possible causes. Traditionally, statistical inference is performed under the assumption that the failure causes act independently on each item. In this paper we propose an EM-based approach which allows for dependent competing risks and produces estimators for the sub-distribution functions. We also discuss identifiability of parameters if none of the masked items have their cause of failure clarified in a second stage analysis (e.g. autopsy). The procedures proposed are illustrated with two datasets.

Algorithms↗

PubMed2003

Addition and expansion theorems for complete orthonormal sets of exponential-type orbitals in coordinate and momentum representations.

Analytical properties of new complete orthonormal sets of Psi(alpha) exponential-type orbitals (Psi(alpha)-ETOs where alpha=1, 0, -1, -2, em leader ), introduced by the author as finite linear combinations of Slater-type orbitals (STOs), are studied. Addition and expansion theorems for Psi(alpha)-ETOs are obtained in both coordinate and momentum representations. Using expressions of Psi(alpha)-ETOs in terms of STOs, the new methods are suggested to calculate multicenter multielectron integrals over STOs.

Algorithms↗

PubMed2003

An EM-based semi-parametric mixture model approach to the regression analysis of competing-risks data.

We consider a mixture model approach to the regression analysis of competing-risks data. Attention is focused on inference concerning the effects of factors on both the probability of occurrence and the hazard rate conditional on each of the failure types. These two quantities are specified in the mixture model using the logistic model and the proportional hazards model, respectively. We propose a semi-parametric mixture method to estimate the logistic and regression coefficients jointly, whereby the component-baseline hazard functions are completely unspecified. Estimation is based on maximum likelihood on the basis of the full likelihood, implemented via an expectation-conditional maximization (ECM) algorithm. Simulation studies are performed to compare the performance of the proposed semi-parametric method with a fully parametric mixture approach. The results show that when the component-baseline hazard is monotonic increasing, the semi-parametric and fully parametric mixture approaches are comparable for mildly and moderately censored samples. When the component-baseline hazard is not monotonic increasing, the semi-parametric method consistently provides less biased estimates than a fully parametric approach and is comparable in efficiency in the estimation of the parameters for all levels of censoring. The methods are illustrated using a real data set of prostate cancer patients treated with different dosages of the drug diethylstilbestrol.

Algorithms↗

PubMed2001

Effectiveness of computational methods in haplotype prediction.

Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.

Arylamine N-Acetyltransferase↗

PubMedDate not supplied

Can current EMS dispatch protocols identify layperson-reported sentinel conditions?

INTRODUCTION: Managed care organizations are seeking opportunities to capitate for emergency medical services (EMS). These and others pressures are motivating EMS planners to find innovative ways to redeploy existing EMS resources. A successful redeployment of resources implies a mechanism for more carefully matching EMS resources to need than currently exists. OBJECTIVE: To determine whether the methods dispatchers currently use to assign nature codes (NCs) and severity codes (SCs) also can distinguish between patients with important sentinel conditions and those without. METHODS: This was a six-month prospective study (June to November 1997). Portland Fire Bureau (PFB) paramedic units documented dispatcher-assigned NCs and SCs and the presence or absence of study-established sentinel findings. The PFB paramedics also verified or corrected dispatcher-assigned NCs and SCs using dispatch algorithms identical to those in use at this urban dispatch center. Cross-tabulation tables (SPSS version 6.1) with chi-square statistics were established to illustrate the relationship between SC strata within specific NCs and the presence or absence of sentinel findings. RESULTS: One thousand two hundred eighty-five usable cases fell into 25 unique NCs. The designation SC 1 (emergent) was assigned by the dispatcher 307 (24%) times, SC 3 (urgent) was assigned 907 (71%) times, and SC 9 (neither emergent nor urgent) was assigned 26 (2%) times. The SC was missing 45 (3%) times. The PFB records were matched to 1,040 (82%) dispatch records. Sentinel conditions were identified in 411 (40%) of these cases. Eight (32%) of 25 NCs were stratified into two or more levels of dispatcher-determined SCs. One cross-tabulation table for each of these eight NCs was developed to display the relationship between SC strata and the presence or absence of a sentinel condition. Five tables produced statistically significant chi-square tables (p < 0.05). None achieved the study-specified level of 95% sensitivity. CONCLUSION: Current dispatcher-assigned NCs and SCs do not appear adequate to detect callers with study-developed sentinel criteria.

Aged↗

PubMed2002

Prehospital care of the stroke patient.

Acute stroke care is a multidisciplinary effort. It crosses the boundaries of traditional hospital-based medicine, relying heavily on prehospital providers to obtain a significant amount of clinical information. Currently, modifications of existing EMS systems are underway to support the idea that "time is brain." Dispatchers and EMS providers are vital players in the Chain of Recovery, and are challenged to perform within this new paradigm for acute stroke care. In the near future, optimal management of the acute stroke patient may include the administration of neuroprotective medications in the prehospital setting. Educational efforts targeting high risk and elderly populations also continue to be a priority for healthcare providers and public interest groups such as the NSA. Stroke victims, family members, and caregivers must all be aware of the warning signs and symptoms of stroke. The importance of using EMS during the initial phase of acute stroke cannot be overstated. Emergency physicians must lead in coordinating the resources, placing greater emphasis on educating and assessing the performance of prehospital providers [50]. These leaders must ensure that prehospital providers understand they are integral members of the stroke team, vital to improving stroke care in the community.

Algorithms↗

PubMed2003

Inferring strengths of protein-protein interactions from experimental data using linear programming.

MOTIVATION: Several computational methods have been proposed for inference of protein-protein interactions. Most of the existing methods assume that protein-protein interaction data are given as binary data (i.e. whether or not each protein pair interacts). However, multiple biological experiments are performed for the same protein pairs and thus the ratio (strength) of the number of observed interactions to the number of experiments is available for each protein pair. RESULTS: We propose a new method for inference of protein-protein interactions from such experimental data. This method tries to minimize the errors between the ratios of observed interactions and the predicted probabilities in training data, where this problem is formalized as a linear program based on a probabilistic model. We compared the proposed method with the association method, the EM method and the SVM-based method using real interaction data. It is shown that a variant of the method is comparable to existing methods for binary data. It is also shown that the method outperforms existing methods for numerical data. AVAILABILITY: Programs transforming input data into LP format files are available upon request.

Algorithms↗

PubMed2003

Fast and single solid phase fluorescence spectroscopic batch procedure for (acetyl) salicylic acid determination in drug formulations.

A solid phase fluorescence spectroscopic batch procedure for (acetyl) salicylic acid in drug formulations have been developed. The procedure is based on the sorption of salicylic acid (SA) on Sephadex DEAE A-25 anion exchanger gel (100 mg) by equilibration from an aqueous solution (10 or 25 ml) for 5 min; the equilibrated gel is transferred into an 1 mm quartz cell and the native fluorescence of SA sorbed on it is directly measured (lambda(ex)=297 nm; lambda(em)=405 nm). Good linearity was found in the 10-200 and 5-100 microg l(-1) ranges (for 10 and 25 ml sample volume, respectively) with R.S.D. (%) of 2.8 and 1.1. The procedure was successfully applied to the determination of acetyl salicylic acid (ASA) in drug formulations after alkaline hydrolysis to yield SA.

Algorithms↗

PubMedDate not supplied

Current practice in clinical cervical spinal clearance: implication for EMS.

OBJECTIVES: To examine the practice of clinically "clearing" the cervical spine (c-spine) of trauma patients brought to the ED by EMS with cervical immobilization in place, and to examine developing trends in prehospital c-spine clearance. METHODS: A 12-question survey form was mailed to the physician medical directors of 300 randomly selected EDs. Questions examined ED clinical clearance practices, EMS clearance protocols and research, and attitudes toward prehospital clearance. Estimated clinical clearance rates were requested. RESULTS: A total of 173 surveys were returned (58%). At 21 hospitals (12%), c-spine films are obtained for all immobilized trauma patients; clinical clearance is never attempted. Of the remaining 151 hospitals, on average, clinical clearance is attempted for 65.5% of these patients (range 3-100%, interquartile range 50-100%) and is successful (films are not obtained) for 53.7% of attempts (range 0-100%, interquartile range 35-75%). No differences exist in either attempt rate or success rate between trauma centers and non-trauma centers, or between academic/university hospitals, community teaching hospitals, and community non-teaching hospitals (t-test or ANOVA, p > 0.05). Seventy-two respondents (42%) reported significant variation in clinical clearance practice patterns among their ED physicians. Seventy-three respondents (42%) feel that EMS providers should immobilize all trauma patients, while 99 (57%) feel it is reasonable for trained EMS providers to attempt clinical clearance on low-risk trauma patients. CONCLUSIONS: There is tremendous variation in the ED practice of clinically clearing cervical spines. This, and a lack of support from many ED directors, may hinder attempts at development of research and standardized protocols for pre-hospital c-spine clearance.

Algorithms↗